Halogenated steroid derivatives and process of preparing same



-rivatives of sapogenins and processes for prepar- Patented July 4, 1944 UNITED STATES PATENT oFFI-cE HALOGENATED STEROID DERIVATIVES AND PRooEss or PREPARING SAME Russell Earl Marker, State College, Pa., assignor to Parke, Davis & Company, Detroit, Mich, a

corporation of Michigan No Drawing. Application August 3, 1940,

Serial No. 351,145

18 Claims. 01. 260-2395) This invention relates to halogenated steroidal derivatives and process of preparing same, and more particularly to side chain halogenated deing the same. An object of this invention, therefore, is the 7 preparation of new side chain halogenated steroidal sapogenin derivatives.

Another object of this invention'is the preparation of steroidal sapogenin derivatives useful as intermediates for the preparation of steroidal hormones.

Another object of this invention is the preparation of steroidal sapogenin derivatives having reactive groupings in the side chain.

Other objects of this invention will be apparent from a perusal of the specification and theappended .claims. 1

The naturally occurring steroidal saponins lFieser, Chemistry of Natural Products Related to Phenanthrene, (Reinhold Pub-l. Corp N.'Y. C.,

1936) p. 317 et seq.] may be hydrolyzed to yield sugars and a sugar-free moiety, designated as the aglycorie. The aglycones of these steroidal saponins are designated steroidal sapogenins, and the term steroidal sapogenin is commonly employed byworkers in this field to include also nuclear I transformation products of these aglycones.

These aglycones have, in general, the formula C27I-I42-403-5, of which the portion CeHmOz is known to be present as a sid chain attached to .ring D of the steroid skeleton. Tschescheand Hagedorn (Ber. 68, 2247 (1935)) proposed the formula CH3 CH3 CH3 I f? we CH-CH CH-CH: C D 1) MRI icithe sapogem 'tigegemn, and 1am workers have, with reservations, @Qcepted this formulation of the steroidal sapogenin side chain. Other sapogenins such as digitogenin, gitogenin, chlorogenin, diosgenin, and sarsasapogenin have shown to differ from tigogenin only in regard to the connections between ring A and B, the degree of saturation of the ring system, and the numberofsubstituents attached to these rings.

These differences are shown below:

I have ire'centlysugigested (Marker 8 Rohrmann J. Am. Chem. Soc. 6:1,,846 (1939)) that a more likely structure for the sidechain of these steroidal sapogenins is that shown below.

It is apparent that this formulation differs from that of Tschesche and Hagedorn in that the linkage, Ch -0%, is transferred from C2; to C22.

However, a profounddiilerence in the nature of the functional character of the side chain oxygen atoms is implied, for while the Tschesche-Hagedorn formula is that of? an a, af-di-tetrahydrofury] derivative, the Marker-Rohrmann formula is that of a 'spiro ket'al.

Recently it has been found (Marks? 8: Rammann, J. Am. Chem. Soc. 61, 846, 1516, 2724, 3479, .(1939); 62, 64:1, 8,96 11 62) that the side chain of the naturally occurring sapogenins exists in two modifications. Sarsasapogenin contains I'one type of side. chain characterized by the fact that a sapogenini'o'f this type is readily reduced according to theClemmensen procedure using alcoholic hydrochloric acid and amalgamated zinc (Marker & Rohrmann, J. Am. Chem. Soc. 61, 846 (1939)) to give tetrahydro derivatives, that is to say, new sapogenin derivatives in-which the side chain has 4 more hydrogen atoms than in th sapogenins themselves. Tig ogenin, gito'genin,

digitogenin, chlorogenin and "dios'geni'n'behave difierently from sarsasapogenin in that they are not reduced by the Clemmensen-procedure, that is to say, they are recovered unchanged after boiling with alcoholic hydrochloric acid, and amalgamated zinc. Isosarsasapogenin is convertedunder the conditions of the:Clemmensen reduction to the same tetrahydrosarsasapogenin that sarsasapogenin itself yields; These facts,

and others which are cited inthe references listed, appear to me "to be best explained by assuming that the two types of steroidal sapogenin side chains-'diff-erin regard to optical isomerism about C2 9 Accordingly, whenit is necessary to distinguish between isomers about C22 I represent the two types of side chains by for-= mulae of the following type:

I (flfigogenin type side chain) See especially -Marker, & Rohrmann, J. Am.

, Chem. Soc. 62, 896 (1940). Ordinarily where isomerism about C22 is not of importance, the formula for the sarsasapogenin type of side chain will be used for configurations both of sarsasapogenin and tigogenin type.

These two types of sapogenin side chains appear to be subject to an equilibrium; the velocity of attainment of which is catalyzed by acidic reagents. The equilibrium. is influenced by the,

configuration of the hydrogen atom at C5, and it appears that the following rule holds true. For

compounds of the allo series (cholestane type) the tigogenin type of side chain is the more stable, while for compounds of the regular series (coprostane'type) at. C the sarsasapogenin side chain is the more stable.

. For the purpose-o1; greater clarification, the

; Marker-Rohrmann formulation of the side chain of the steroidal sapogenins will be used in de scribing the invention. It is to be understood, however, that the processes and products of the present invention may be obtained by the use of the methods herein to be described and these processes and products are claimed without any implications that the reactions and structures involved-will ultimately be proved to be as represented herein.

I have found that steroidal sapogenins may be halogenated, under acidic conditions, to give side chain halogenated steroidal sapogenins. Furthermore, I have found that this halogenation occurs with surprising ease, especially when it is considered that the side chain of the steroidal sapogenins has long been considered to be rather inert'to the ordinary reagents of organic chemistry. While I have thus found that the side chain of the steroidal sapogenins is readily monohalogenated, thus far I have not succeeded in introducing more than one halogen atom into the side chain. Furthermore, I find that the halogenation proceeds best in an acidic solvent such as acetic acid, propionic acid or any other of the lower aliphatic acids. These new side chain halogenated sapogenin derivatives Icall halosapogenins. By the term halogen as applied to my new compounds and their preparation, I mean chlorine and bromine,.thereby excluding fluorine and iodine. Fluorine is excluded because of the difliculty of controlling its behavior, while iodin is excluded because of its inertness.

The halosapogenins show certain characteristic reactions which distinguish them fromthe sapogenins themselves. Thus:

(a) Whereas the sapogenins themselves are readily oxidized by selenium dioxide, for example, when the sapogenin is heated for awhilev with selenium dioxide in acetic acid-benzene,'the.slde chain halogenated sapogenins are inert to selenium dioxide under comparable conditions; a

(b). Whereas the sapogenins themselves are inert to certain reducing agents such as zinc dust and acetic acid or sodium and alcohol, the side chain halogenated sapogenins are reduced by these-reagents to the parent sapogenins themselves.

On the other hand, the side chain halogenated sapogenins also show certain reactions in common with the sapogenins themselves. Thus:'

(a) Like the sapogenins the side chain halogenated sapogenins fail to give any tests with the usual reagents for hydroxyl, carboxyl or ketone groups in the side chain;

(17) Like the sapogenins the side chain halogenated sapogenins can be reduced according to the Clemmensen procedure, especially using alcoholic hydrochloric acid and amalgamated zinc, to give tetrahydrosapogenins;

(0) Like the sapogenins themselves the side chain halogenated sapogenins can be catalytically hydrogenated to give dihydrosapogenins.

It is to be understood that the reduction of the side-chain halogenated sapogenins to the dihydrosapogenins proceeds in two steps as follows:

sidechain halogenated sapogenin mild reduction (step 1) sapogenin more vigorous reduction (step 2) dihydrosapogenin V As already indicated, step 1 is accomplished by also beaccoinplishedby controlled catalytic hydrogenation, as innxampie 5. -Stp-2is-'accomplishe'd by more vigorous reduction-"the best results usually being obtained by vigorous catalytic "hydrogenation, usually above room temperatures.

Obviously, the application of this mode of reduction to the side-chainhalogenated sapogenins yields thedihydrosapogenins directly. i

- Advantage of step 1 may be taken to prepare nuclear transformation products I having the sapogenin side-chain; The 'sapogenin side-chain is readily attacked by, many reagents including lenmm,dibx ahmw peroxidebromihe a othr reagents reactivewith ketones; since the monohalogenated side cha'in 'i's inert, to reagents of this type, the presencefo'f the's'ide chain halos e weay. be i fi ed "a a m a of P a s tion for the side-chain, while nuclear transforma- }(C ibxL 2 I where")? is a member of the class consisting of chlorine and bromine, where the symbol nA represeats n carbon-to-carbon double bonds in the 'AB portion of the steroid nucleus; n having one of the values 0, 1, 2 an'dS, and where the symbol mY represents m substituents attached 'to-the methylene carbon atoms of the A-B portion of the steroid nucleus',*=said substitu'ehtsbiaing se- "lec'te'd from 'the'class consisting of 'fit'hav'ing'one ofithe values 0, 1 ,2-and 3, m and n being "so chosen that their sum m+ndoes 11 11 X- "ced the value 3.

While I d'o'not Wish toibelirniteditofany specific formula for 1. my 'new2side .chainhalogenated sa'pog'enin derivatives, I believe thatxthe'ploperties of these substances are best explained by one of the two following typesof formulae illustrated for the casei of a side chain -=jhalogenated ;sarsa-.

.one mole, or a slight excess, of the free halogen, either chlorine or bromine, referably in an orgame solvent. mere short time the react "is complete and the side chain halogenated apoemn derivative may be isolated according to .the methods best adapted t thepropertie'sfof derivative thus formed. My y. followin'g'eira'rnplesi the particular side chain halogenated "sa ogenin on may be further illustratedby the Erample, 1

1 g.'of cc. o f 1glacia1 acetic acid and the solution 7 ed to C. Then'two drops of '48%h'yd'ro romic acid is added and the mixture treated wit 2 'cc. of 1:05 molar bromine in'a'cetic acid solution over "a period of ten minutes. The'bror'nine is readily taken up with liberation of hydrogen bromide. After the mixture has stood for ten minutes it is pouredinto water and the precipitatedmaterial 'iiltered aiid washed with water, The residue is i "ff 3' j 'i'l. ac a 1 i'i needlesiiiel'ting at 208? 'C.' -withxie- On larger runs, the brdmosars'asapogeninacetate maybe obtaified'a's large white prisms' 'me'lt- 'in'g at195 c with v d' oiriposition. This' substameappars to beidentical withtlie brb'mbsarfsasfaisdg mn acetate, l eltin'g point 208 0. described above, for it has thesa 'ne' composition and "behaves the same in the Various reactio'ri s cajriled out withit. i V p Y g nsteaa of using sarsasapogeriin acetate, other esters of sarsasapog j I the benzoate may used in this exam m:

7 Example -2 (d l rsosar as ps egnm acetate is prepared accordingtdthedirections of Marker and Rohr- 'cainpdsm mam; J. Am. Chem. Soc. 61,- 846 (1939) b 'fIo a" solution of 1 g. of isosarsasapdenin acetate in cc. offgla'c'ial acetic acid at 20 C.

-' is'addedtwo drops of 48% hydrobromic'acid,then

the solution is treated with 2.2 cc. of L05 molar 1 loromine in a etic acid 'solution over aperiod of tn minute's. Bromine is readily taken up with liberation of "hydrogen 'bromide, After ten minutes the mixture is poured into Water and-the precipitated material collected! and washed with water.- This solid product is crystallized-from "acetate of the previousexample, and'itdepres'ses in r'rielti'n'gfpoint with preparations time: previ- *rsas apogenin acetate is dissolved 35 y in, such as thetutyrate or V It is thought that fbromosarsasapogenin acetate is isomeric with bromoisosarsasapogenin acetate. 4 I .drogen bromide. After twenty minutes the mix- E m le 3 i p I .tureis=poured,into-water and the precipitated To a solution of'l00 g. of-epi sarsasapogenin Solids collected, andtwrashed. withv The acetate (prepared for example as described by ,dried crude product crystallizeifmm aqueous Marker & Rohrmann', '{Q F s 61, 943 acetone to givewhite needles which begin to de- (1939)) in cc. of glacial acetic acid is added compose at about I i i one drop of 48% hydrobromic acid. Then to the a when the Nomination of sarsasapogefim; mixture is added 025 cc. of 1.05 molar bromine in carried outrun a somewhat larger scale 4 g. acetic acid. After standing a few minutes the lots) the reaction mixture often becomesidep solution is poured into water and the precipitate bluednqcolorm E ,oollected, washed withiwater anddried; The white'isolid is"'crystallizfed1'from acetone to give small white plates of 'meltii'i'gpoi' 130: c; L'Ihis, is broino epi-sarsasapoghin ae'ta 1- '1. .Example'.4--:

f (a') Desoxysarsasapogenin is prepared" asj'ior example by Marker 81 R'ohrmann, J; Am. Chem. Soc. 61, 1284 (1939).

f '(b). .1'T 0 a solution of 100 mg. of: desoxysarsasapogenin in 60 cc. of glacial acetic acid acidifiied with five drops of 48% of hydrobromic acid is added 025 cc. of 1.05 molar' b'romine 'i n'glacial acetic acid. The bromineis takenup'Withdiiii bromine in acetic solution. The bromine, is

.E:rarn 1ole7 The side chain of the sapogenins is frequently more readily brominated than a methylene group adjacent to a nuclear 3'-,keto group; This is shown in the following example.

' A solution of 1 'g'. of sar'sasapogenone in 35 cc. of glacial acetic acid is cooledto C; and acidif ed with two drops of .8%hydrobroinic acid. Then 2.2 cc. of 1,05 molar bromine in acetic acid is added dropwise' over a periodof ten minutes.

.The bromine is readily absorbed with liberation of hydrogen bromide. The mixture ispoured jnto. water, the precipitated solids collected,

talge'n uprather readily withfliberation of sasapogenin.

To 200mg. of j .glacial'acetic acid' containing two drops of 4 l% 'culty, but after standing about fifteen minutes all of it has been absorbed. Then th solution is poured into water and: the precipitate collected and washed with water.. .The dried vmaterial is crystallized" from acetone to give 'white crystals, m ti gi 1 T m assie- ,This substance shows no evidence o .when heated for thirty minutes withselehium dioxide in acetic acid-benzene Emmple5 1..

tigogenin acetate 3O I cc. of

hydrobromicacid is addedat room temperature 0.5 cc. of 1105 molar bromine in gla acid. The bromine is taken up rather washed with water and dried. The dried residue is crystallized from acetone togive white crystals of melting point 190 C. with. decomposition.

IThis' is br omosarsasap'ogenone, in' which the bromine atom is in the side chain.

To show that the bromine atom of b'r'omosarsasapogenone is in the side chain and in order to show an alternative mode of preparation of bromosarsasapogenone, the following experiment may be performed. v

To a solution, of 100 m of mO- sarsasapogenin in ccaof glacial acetic acid is added 300 mg. of chromic anhydride in 10 cc. of acetic acid. After the mixture has stood at room-temperature for forty-five minutes, it

poured into water, the precipitated material extracted with ether, and the ethereal extract I "after about fifteen minutes the reaction'is complete. Thenthe solation'is dilutedwith water H and the precipitate. collected, washed with water washed with sodium carbonate solution and we- 2- ter. The ether is evaporated on the steam bath and the residue crystallized from acetone tog ive andfdriedfi The product is 'crysta-llixedflfrom acetone to give white needles of bromotigogenin f acetate ofmelting point 223 C. withdeco nposi- ;.=pale =tan needles of melting point 191. C .wi th decomposition This is bromosarsasapo'genone and it gives no depression inmelting pointwhen 'ti'on. This substance shows no evidence "of oxidation when heated, for twenty 'minutesat, CLjwith "seleniiiin'dioxid'e inajcetic acid'j". i Q

The side chain halogenated "sapogenin derivatives are readily reduced-to the parent sapogenins by, catalytic hydrogenation in acidicsolution or hyreduetion with an alkali metalandan alcohol. To illustrate the latter mode of reductionasolu- .-.ti 0f-50 .m q hrpmot min ai s e in 50 ji cc.- of boiling absolute alcohol maybe reduced by adding two g. of ,sodiumover a period i f ortyfive, minutes, The solution is diluted w th wa- .-.ter,fth,e precipitated solids taken up in ethe the :fretherdayer; separated and washed with;waten and .-the ether--.evaporated.-- -'Ihe residuegis crystallized from methanol to givesmallwhiteplatespf melt- 1 ing :p0int'202-203' CwThis is tigogenin and it gives no depression in meltingpoint when mixed withan authentic :sample:

mixed with a sample prepared by the bromination of sarsasapogenone.

Example 8 'sarsastpogenon; belting point 190 compoistion.

(b) Five grams of dibromosarsasapogenone prepared as described above is dissolved in 50 cc.

o. with-dethe end-of this time some crystalline material which has separated, i s filtered off, washed with water and dried to give small.whitecrystals, of melting point 235 C. with decomposition. This product is probably a pyridiniumof saltof dibromosarsasapogenone. J

A solution 0% 820 mg;of1sarsasapogeni i to o l ia ac ic c d is-se le $0 9? G.- e *ztwo drops oih dmbrom a d-i ded .issolution is *tr ated'iwithz 21.3%": 5,1

much hydrogen bromide is liberated. .i The solugives small compact white crystals of dibromoof dry pyridine and refluxedforeight hours. At

The filtrate from the above separation of the n id mf m alt s our t di lfuri acid and the. precipitated solid taken up in ether. The ethereal solution is treated with Norite,

evaporated, and the residue crystallized from acetone to give small compact white crystals of melting point 185.-188 C. with decomposition.

Bromd-A-dehydrosarsasapogenone (c) To a boiling solution of 2 g; of bromo-A dehydrosarsasapogenone (prepared as described above) in 400 cc. of absolute alcohol is added 17 g. of sodium over a period of one hour. Water s added and th P e ipitated. sc iq ieken p i sma t. W sh d w l th. Wa and h e he vaporated; Ther sisiual Sims is l ed n b ut c- Q alcoh l nd added o asolution Qfiii e- 91?, dis ton n, in 300cc f 8 a ho he in olub e ieito e h ch s ra i 60 lected, washed with ether and dried. The dried digitonide is heated for twenty minutes with SO;

cc. of pyri neon a steam b I v Th nthe soluio l-111 i;

. d wi weer.. extrac ed w t t er and the ethereal layer washed well with dilute;

Example 9 To as lu ion o 00 e. oi itoeenin iiace a n 39 c of acet c aci a i ified wit two d o of 48%: hyd b mic acid is added 0.6 cc.. of; 1.05 mme in acet aci -v A t r h m x u for a short time it is diluted with water the preci itateq l ected wa hed with w te and dried-e. i lerdriednr d qtis crysta ized om acetonemethanol to give white needles of brpmoe gitogenin diacetate, melting point 219-220 C. with decomposition.

The bromogitogenindiacetate of this example may be reducedwith sodium and absolute alcohol in -a manner similar to that given in Example 5, to obtain gitogenin of melting point 265-267 C.

The bromogitogenin diacetate of this example shows no evidence of reaction when heated with an acetic: ac d so ut on o selen mndip i e :Exdmfie 1'0 I 1- Tea solu ion: r 0 di oe mn. .triaceta ein 39 cc. of acetic acirij acidified. with WI. ODS" of 48%. hydrobromic acid is added.(l.55' rs, .f: 1. mo r bromin ace c-ac d. {The mix ur a l wed to so d-i n about twentyminutes and'then is poured into wate t es with e her. n e e htteel la z arated, washed with water and evaporated .to dryness, The residue is crystallized fromaqueous methanol to give white crystals of bromo digitogenin triacetate of :rnelting point 142 C. with decomposition.

Its-behavior toward ies a dioxide and tosodiumandalcohol is analogous tothat of loromogitqgenin diacetate and other'side chain halo en ed emce -ru n Of, th s i v nt A 'Eammp'le 11 i T' a Sfl lfiQ -ibf 5, man; hlorogenin d a ea 4 cc! f. laei l' a et a id co n two drops of" concentrated. hydrochloric acid is ddcd'lil cc. ofj 1.Q5'mo1 a r bromine in acetic acid as rapidly as the'bromine is absorbed. Then e vqi meltin pp h arsasanpgsny c m gsanq he f the solutior'iispoured intowaterpand the precipitate co lected. and washed, with water. "The ed sidue .i ry tall zed fr m me h nol to give white crystals oi bromqfihlor enin, diace:

Q0?v c; with, sli ht} decomv2 1 61 a (a). 'Sarsasapogenyl chloride-is prepared ac cording to the directions of Simpson &":-Jac.obs,- J. Biol. Chem. 110, 5.65. (1935); c I

1 (-11): 1 gtof' sarsasapo'genyl chloride;-in-,35 cc. of chloroform is-diluted with 10 cc. of acetic acid and 3 drops off48%.;hydrobromicracid are added.- To this mixture ,is added slowly a ,solution'of 0.15 g. of dry chlorine-gas in 20; cc. of=l::-1 acetic ac'd chloroform. After the mixture has stood to n-houritis pouredinto, Water; extracted" with; chloroform and--the -chlorof0rm, solution washed: with; water. Ihechloroform is removed n the s eamibath a d the 'residuewcrysta lized from slightly diluted methal-lql to .giveychloroarsas po e yl h or de .in-the form f! 1 white c ystal .j' lhi r om ound-may be renres nted by ut, a s'mthe'ir 'mi f eme meann s -inl derived from the aglycone b A {a ti/9;: 2-3 w ich: l av n a tf nd tached to ring n-t geaslvcon sh I S this inven iqn- 11 medi al t r ida s ieil s' um a mile genin, 'sarsasapogenone, 3-desoxysarsasapggenin,

- As ist s ate b samp s an enins having either configuration with o C zf heim-is mosey-stapes tigogenin type of side chain--may be side chain halogenated to give the corresponding isomeric side chain halogenated sapogenins.

It will be apparent that in practicing my invention on certain types of sapo'genins, transformations may occur in the nucleus in rings A and B as well as in the side chain. For example, if nuclear ketone groups are present, the; products obtained by the practice of my invention are dependent upon the conditions employed. Thus in the case of sarsasapogenone I have found that the use of 'only one mole of ,h'alog'en-. ating agent leads to the Iormation almost ex-' clusively of the side chain halogenated sapogenin compound. But if a second mole of halogenating agent be added to thereactionmixture, this side chain halogenated sapogeninv compound is further halogenated in the nucleus on, a carbon atom adjacent to the reactive ketone group, I

forming dibromosarsasapogenone.

Again diosgenin on halogenation according to my invention absorbs two moles of bromine to form bromodiosgenin dibromide in which two bromine atoms have been added to the double bond at C5.

Generalizing, I have observed" that" nuclear hydroxyl groups, or their hydrolyzable derivatives such as -Oacyl, '-Oarall:yl and halogen, are'not affected, but double bonds and reactive ketone groups in the nucleusin rings A and B are transformed as suggested above. That" is to say, a methylene group adjacent to a reactive nuclear ketone'group is halogenated after the side chain of the sapogenin has been hal ogenated', while nuclear double bonds add halogen' simultaneously with the 'halogenation of the sapogenin side chain.

Other modes of isolating and purifying the side chain halogenated sapogenins of this invention may be used instead of extraction with ether and What I claim smy invention'is'; f, f

, 1 .Plro'cess for] Preparing af'halosapogen'in which comprises subjecting a'steroidal sapogeninv to the action of a member f the classconsistin of chlorine and bromine, 'thefquantity ofhalogen being atleast one equivalent of halogen in excess of that which will reactjwith any nuclearl double bonds in said steroidalsapogenin, there'- by forming a steroidal sapogenin having a monohalogenated side-chaing'm} 2;. Process iaccording tio' iclaim' 1 wherein the 1Inalogenati on is 1condu cted under acidic condilons.

3. Process according to claim 1 wherein the halogenation is conducted in the presence of an organic acid; '1 4. Process according "to claim 1 wherein the halogenation is conducted in the', presence of a ti acidy iij 1 *5, Process according to claim where" thehalogenatingagent'is'bromine.

6 time which comprises subjecting a compound'hav to the action of .amember "stantially only one mole of halogenating agent'- side-chain;

*6. Process for preparing a halosapogenin which comprises subjecting to the action one member of the class consisting of chlorine'andi bromine a compound having theformula,

where the symbol nA represents 11. carbon-tocarbon double bonds in the AB portion of the steroid nucleus, 11. having one of the values 0, 1, 2 and 3, and where the symbol mY represents m substituents attached to the methylene carbon atoms of the A-B portion of the steroid nucleus, said substituents being selected'from the class consisting of (=0);

m having one of the values 0, 1, 2 and 3, n being so chosen that their sum, m-l-n, doesno't" exceed the value 3, the quantity of halogen" being at least one equivalent of halogen in excess cr' that which will react with any nuclear double; bonds in said steroidal sapogenin, thereby'forming a steroidal sapog'enin having a 'mono'jbrominated'si'de-cliain.

7'.' Proces's for preparing a sapogenin'derivae O'acyl halogen 1 and 1 ing'the formula, v

on. em

JICaHMOD I V I 'I of the class consist ing of chlorine and bromine, thereby forming a sapogenin derivative halogenated at least in the side-chain. v I

8.*P'rocess according to claim 7 in which subis employed, thereby forming a nuclear-nun ogenate'd side chain halogenated sapogenjfi age: rivative. v

9. Process for reparing a halosapogeninwhich 3 comprises subjecting I a compound the formula, V 1

" CH3 CH3 l e i ll where Y is selected from the class consisting'bf hydroxyl and groups hydrolyzable to hydroxyl,

to theaction of a member of the classconsistingof chlorine and bromine the quantityv 9f;

halogen beingat least one equivalent of halogen in excess of that which will react with nuclear 7 double bonds; in said compound, thereby form e'e sap en 10'. Process accordingto 615ml 9 whereimthe derivative halogenatedfin the a sapogenin halogenated is selected from the group consisting of sarsasapogenin and its esters.

11. Process according to claim 9 in which the halogenating agent is bromine.

12. A side-chain mono-halogenated steroidal sapogenin derivative having the formula,

CH3 CH3 \/\/v where X is a. member of the class consisting of chlorine and bromine, where the symbol 12A represents n icarbon-to-carbon double bonds in the AB portion of the steroid nucleus, n having one of the values 0, 1, 2 and 3, and where'the symbolt mY represents m substituents attached to the methylene carbon atoms of the AB portion of the steroid nucleus, said substituents being selected from the class consisting of (:0),

- brominated sarsasapogenin ester being identical with the product obtained by reacting the corresponding sarsasapogenin ester with bromine in acetic acid.

14. An iso-sarsasapogenin ester, having a monobrominated side-chain characterized in that the side-chain (C8H15BIO2) is unaffected by selenium dioxide in acetic acid, and in that the side-chain (CaHrsBIOz) is reduced to the sapogenin side-chain (CGH1602) by the action of the combination of sodium and alcohol, said sidechain monobrominated iso-sarsasapogenin ester being identical with the product obtained by reacting the corresponding iso-sarsasapogenin ester with bromine in acetic acid.

15. Sarsasapogenin acetate having a monobrominated side-chain, melting with decomposition at approximately 208 C. and approximately 195 C.

16. Iso-sarsasapogenin acetate having a monobrominated side-chain, melting at approximately 170 C. 7

1'7. Sarsasapogenone, having a monobrominated side-chain melting with decomposition at approximately 191 C.

18. A side-chain mono-halogenated steroidal sapogenin having at ring D the structure,

RU S L E R MARKER, 

